Objective: Epithelial ovarian cancer (EOC) has a poor prognosis because of high recurrence rate due to chemoresistance, and there is a need to find new therapeutic drugs. Previous studies showed antipsychotic drugs to have anticancer effects. In this study, we investigated the anticancer potential of penfluridol, an antipsychotic drug used in schizophrenia, on ovarian cancer cell lines. Methods: In vitro, EOC cell lines were treated with penfluridol and cell survival was assessed using MTT assay. Furthermore, we evaluated the synergistic effect of penfluridol with paclitaxel on EOC cell lines. In vivo experiments were performed to test the effect of penfluridol and paclitaxel combination on tumor growth in orthotopic mouse xenografts of EOC cell lines. Results: Penfluridol significantly reduced cell proliferation in chemosensitive (A2780, HeyA8, SKOV3ip-1) and chemoresistant (A2780-CP20, HeyA8-MDR, SKOV3-TR) EOC cells with time and dose dependent manner. In chemoresistant cell lines (HeyA8-MDR, SKOV3-TR), penfluridol and paclitaxel combination showed significantly reduced cell proliferation compared to the control, paclitaxel alone, or penfluridol alone. In xenograft mouse models of EOC using HeyA8, mice treated with penfluridol showed significantly reduced tumor weight compared to control group, but showed similar effect with paclitaxel alone or penfluridol and paclitaxel combination group. In model with HeyA8-MDR, mice treated with the combination of penfluridol and paclitaxel had significantly decreased tumor weight than the control, paclitaxel alone, or penfluridol alone groups. Conclusion: Penfluridol might be a potential therapeutic drug for EOC, especially by combination with paclitaxel in chemoresistant ovarian cancer.